WO2017081703A4 - In-silico method to identify combinatorial proteins as immune-stimulators against leishmaniasis - Google Patents
In-silico method to identify combinatorial proteins as immune-stimulators against leishmaniasis Download PDFInfo
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- WO2017081703A4 WO2017081703A4 PCT/IN2016/050390 IN2016050390W WO2017081703A4 WO 2017081703 A4 WO2017081703 A4 WO 2017081703A4 IN 2016050390 W IN2016050390 W IN 2016050390W WO 2017081703 A4 WO2017081703 A4 WO 2017081703A4
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- WIPO (PCT)
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- proteins
- apc
- cell
- response
- regulating
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G16B5/10—Boolean models
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Biophysics (AREA)
- Theoretical Computer Science (AREA)
- Medical Informatics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Bioinformatics & Computational Biology (AREA)
- Biotechnology (AREA)
- Evolutionary Biology (AREA)
- General Health & Medical Sciences (AREA)
- Physiology (AREA)
- Analytical Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a combination of proteins influencing the survival of the Leishmania species inside the human cell and a process for regulating the expression the combination of proteins. Further, the present invention relates to the regulation of the combination of proteins to serve as immuno-stimulators to treat leishmaniasis.
Claims
1. An in-silico method to identify combinations of proteins which are involved in action of a drug useful for treatment of leishmaniasis comprising the steps :
(i) reconstructing Leishmania-APC-T-cell pathway model by integrating intercellular and intra-cellular signalling events occurring between APC (Antigen Presenting cells) and T cell during Leishmania invasion;
(ii) simulating the Leishmania-APC-T-cell pathway model reconstructed in step (i) by AND, OR and NOT logical gates in infected and uninfected scenarios to obtain immune responses in equations selected from the group consisting of;
TH_l_response*= IL2_T AND GM_CSF_T AND TNF_ALPHA_T AND IFN GAMMA T .... (Eq. 1 )
TH_2_response*= IL4_T AND IL5_T AND IL6_T AND IL10_T ... (Eq. 2) NO_response*= NO .... (Eq. 3);
(iii) validating the immune responses as simulated in step (ii) with published literatures to confirm their acceptability and authenticity to obtain validated immune responses;
(iv) perturbing (different proteins by assigning ON/TRUE and/or OFF/FALSE to up regulate or down regulate the phenotypic functions) the validated immune responses of step (iii) to identify immuno- stimulating proteins each from APC and T-cell respectively;
(v) performing single in silico knock in/knock out mutation of the proteins identified in step (iv) to obtain in silico up-regulation/down-regulation of expression of the selected proteins;
(vi) recognizing a combination of the up-regulated/down-regulated proteins as potent immuno stimulators post in silico mutation analysis in step (v) and devising their regulation to yield an effective anti-leishmania response.
35
2. The method as claimed in claim 1, wherein the combination of proteins comprises of three T-cell and two APC molecules.
3. The method as claimed in claim 2, wherein the T-cell molecules are selected from the group consisting of MKP_T, SHP2_T, and SHC_T.
4. The method as claimed in claim 2, wherein the APC molecules are TLR3 and TLR2.
5. The method as claimed in claim 1, wherein the Leishmania- APC-T-cell pathway model comprises 293 nodes, 82 APC molecules, 206 T-cell molecules and 5 Leishmania related molecules.
6. The method as claimed in claim 1, wherein simulating the model in step (ii) results in three phenotypic functions "TH_l_response" (Eq. l), "TH_2_response"(Eq. 2) and "NO_response (Eq. 3).
7. The method as claimed in claim 1, wherein the in silico knock in/knock out of the selected proteins of step (v) are assigned ON/TRUE and OFF/FALSE to up regulate or down regulate the phenotypic functions as claimed in claim 6.
8. The method as claimed in claim 1, wherein the combination of immuno- stimulators of step (vi) is selected from the group consisting of Toll like receptor-2 (TLR-2) and Toll like receptor 3 (TLR-3) in Antigen presenting cells (APC's), Src Homology 2 phosphatase (SHP2) in T-cells, or Mitogen activated protein kinase phosphatase (MKP) and SHC in T-cells, for simultaneously regulating nitric oxide (NO) production, TH1 immune response and TH2 response to expedite clearance of Leishmania pathogen from an infected host cell.
9. The method as claimed in claim 8, wherein a process to increase NO production and TH1 immune response and inhibit TH2 response simultaneously in a Leishmania infected host cell comprises regulating at least one combination selected from: (a) up regulation/stimulation of TLR3 in APC and down regulation/inhibition of SHP2 in T-cell; and
(b) up regulations/stimulation/activation of TLR3 in APC, MKP in T-cell and down regulation/inhibition of SHC in T-cell.
10. Use of the combination of proteins as claimed in claim 2 to treat cutaneous leishmaniasis.
11. Use of the combination of proteins as claimed in claim 2 to control Thl/Th2 immune response during leishmanial infection and to eliminate the parasite from the system.
12. A method for treating leishmaniasis comprising regulating at least one of the combinations of immune-stimulators as claimed in claim 8, wherein the combination is selected from:
(i) up regulating TLR3 and down regulating of SHP2, and
(ii) up regulating TLR3, MKP and down regulating SHC, wherein said method comprises:
(a) up regulating TLR3 by administering agonist Rintatolimod,
(b) up regulating MKP by administering agonist JWH015,
(c) down regulating SHP2 by administering Actinomycin D, and
(d) down regulating SHC by administering 8-hydroxy-7-(6-sulfo naphthalene-2- yl)diazenyl-quinoline-5-sulfonic acid.
STATEMENT UNDER ARTICLE 19(1)
With reference to the search report and written opinion of the International Searching Authority [ISA/EP], we are suitably amending the claims to improve their clarity and to establish the novelty and inventive step in the present application.
1. Claims 1-2 have been suitably amended.
2. Claims 3-5 remain unchanged.
3. Claims 6-7 have been suitably amended.
4. Claims 8-9 remain unchanged.
5. Claims 10-11 have been suitably amended.
6. Claim 12 remains unchanged.
7. Any addition in the claims has been indicated by underline and any deletion in the claims has been indicated by strike through.
The Applicant undertakes that no new subject matter has been added in claims and the amended claims do not go beyond the disclosure of the international application as-filed and have no impact on the description and drawings as filed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15/776,008 US20200020414A1 (en) | 2015-11-12 | 2016-11-09 | In-silico method to identify combinatorial proteins as immune-stimulators against leishmaniasis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3691/DEL/2015 | 2015-11-12 | ||
| IN3691DE2015 | 2015-11-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2017081703A1 WO2017081703A1 (en) | 2017-05-18 |
| WO2017081703A4 true WO2017081703A4 (en) | 2017-07-13 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2016/050390 WO2017081703A1 (en) | 2015-11-12 | 2016-11-09 | In-silico method to identify combinatorial proteins as immune-stimulators against leishmaniasis |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US20200020414A1 (en) |
| WO (1) | WO2017081703A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100160413A1 (en) * | 2008-10-23 | 2010-06-24 | Hemispherx Biopharma, Inc. | Double-stranded ribonucleic acids with rugged physico-chemical structure and highly specific biologic activity |
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2016
- 2016-11-09 US US15/776,008 patent/US20200020414A1/en active Pending
- 2016-11-09 WO PCT/IN2016/050390 patent/WO2017081703A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| US20200020414A1 (en) | 2020-01-16 |
| WO2017081703A1 (en) | 2017-05-18 |
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